The 454/Roche GS-FLX pyrosequencer will be used for high-throughput DNA sequencing in applications demanding long reads (>400 nt) at high accuracy. The technology and characteristics of this sequencing technology is markedly different than for sequencers such as the Solexa/Illumina Genome Sequencer, which provide short (<75 nt) read lengths with a higher error rate. The ability to obtain long read lengths with high accuracy affords several critical advantages for a number of applications, including (1) the sequencing of novel genomes, (2) EST and transcriptome characterization in organisms lacking a sequenced or well-mapped genome, and (3) the analysis of alternative pre-mRNA splicing. The 454/Roche long-read sequencing technology will be applied to a diverse array of NIH-funded projects as well as other projects of high relevance to biomedical science, including the characterization of multigene families involved in sensory perception;the elucidation of the patterns and mechanisms of alternative pre-mRNA splicing;the characterization of genomes of genetic and evolutionary models of human development and disease;an analysis of the genetic loci associated with cancer;and an investigation of the susceptibility of mammalian cells to nutritional ions and environmental toxins. There are currently no 454 DNA sequencers on the UC Berkeley campus;acquisition of this instrumentation by the FGL will support researchers pursuing these projects, which promise to illuminate the fundamental mechanisms underlying human biology and disease.